How I treat Philadelphia chromosome-like acute lymphoblastic leukemia in children, adolescents, and young adults

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) represents a high-risk B-lineage ALL subtype characterized by adverse clinical features and poor relapse-free survival despite risk-adapted multiagent chemotherapy regimens. The advent of next-generation sequencing has unraveled the diversity of kinase-activating genetic drivers in Ph-like ALL that are potentially amenable to personalized molecularly-targeted therapies. Based upon robust preclinical data and promising case series of clinical activity of tyrosine kinase inhibitor (TKI)-based treatment in adults and children with relevant genetic Ph-like ALL subtypes, several clinical trials have investigated the efficacy of JAK- or ABL-directed TKIs in cytokine receptor-like factor 2 (CRLF2)/JAK pathway-mutant or ABL-class Ph-like ALL, respectively. The final results of these trials are pending, and standard-of-care therapeutic approaches for patients with Ph-like ALL have yet to be defined. In this How I Treat perspective, we review recent literature to guide current evidence-based treatment recommendations via illustrative clinical vignettes of children, adolescents, and young adults with newly diagnosed or relapsed/refractory Ph-like ALL, and we further highlight open and soon-to-open trials investigating immunotherapy and TKIs specifically for this high-risk patient population.

Graphical abstract

Figure 1.

Prevalence of Ph-like ALL and distribution of major Ph-like molecular subgroups across the age spectrum. NCI, National Cancer Institute; SR, standard risk.

Figure 2.

Current Ph-like ALL diagnostic algorithm for children, adolescents, and young adults. Diagnostic approach of Ph-like ALL may include initial screening of the kinase–activated Ph-like gene signature by an 8-gene LDA followed by detailed molecular testing to identify specific kinase-activating alterations for cases LDA-positive for the Ph-like gene signature. Alternatively, direct identification of targetable kinase-activating alterations can be achieved via various cytomolecular modalities, including flow cytometric analysis of increased TSLPR (encoded by cytokine receptor-like factor 2 [CRLF2]) cell-surface staining, FISH, single-plex or multiplex reverse transcription polymerase chain reaction (RT-PCR), or NGS.

Figure 3.

Treatment algorithms for de novo Ph-like ALL. Suggested treatment algorithms for pediatric and AYA patients with (A) newly diagnosed ABL-class Ph-like ALL and (B) CRLF2/JAK Ph-like ALL. Common ABL-class fusions involve rearrangements of ABL1, ABL2, CSF1R, or PDGFRB. Uncommon provisional ABL-class fusions involve rearrangements of KIT, LYN, and PDGFRA. CRLF2/JAK pathway alterations involve rearrangements of CRLF2, EPOR, or JAK2, IL7R indels, or SH2B3 deletions. M1 marrow defined as <5% of blasts, M2 marrow defined as ≥5% to 25% leukemia involvement, and M3 marrow defined as >25% leukemia involvement. ∗Please see International Ponte di Legno consensus definitions of ALL treatment response and failure. EOT, end of therapy; TP2, time point 2.

Figure 4.

Treatment algorithms for relapsed/refractory Ph-like ALL. Suggested treatment algorithms for pediatric and AYA patients with (A) relapsed/refractory ABL-class Ph-like ALL and (B) CRLF2/JAK Ph-like ALL. M1 marrow defined as <5% of blasts, M2 marrow defined as ≥5% to 25% leukemia involvement, M3 marrow defined as >25% leukemia involvement. CD19CART, CD19–redirected CAR T cells, CD22CART, CD22–targeted CAR T cells; EOT, end of therapy; TP2, time point 2; TSLPRCART, TSLPR (encoded by CRLF2)–targeted CAR T cells.